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Baseline, post-exposure, absolute change in Ki-67, and difference in absolute change between the ACTOplus met XR and placebo subjects will all be summarized with descriptive statistics. Will compare the difference in absolute change in Ki-67 between the ACTOplus met XR and placebo arms using a two sided two-sample Student's t-test or Wilcoxon rank-sum test, as appropriate, at a significance level of 0.05.

Baseline, post-exposure, absolute change in Ki-67, and difference in absolute change between the ACTOplus met XR and placebo subjects will all be summarized with descriptive statistics. Will compare the difference in absolute change in Ki-67 between the ACTOplus met XR and placebo arms using a two sided two-sample Student's t-test or Wilcoxon rank-sum test, as appropriate, at a significance level of 0.05.

Change in Ki-67 expression in visually normal appearing tissue, assessed by immunohistochemistry [ Time Frame: Baseline to day 26 ]

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Change in Ki-67 expression in visually normal appearing tissue, assessed by IHC [ Time Frame: Baseline to day 26 ]

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

Change in whole transcriptome gene analysis on total RNA samples from visually normal appearing tissue and tumor tissue [ Time Frame: Baseline to day 26 ]

Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.

This randomized phase IIb trial studies how well ACTOplus met XR works in treating in patients with stage I-IV oral cavity or oropharynx cancer that are undergoing definitive treatment. Chemoprevention is the use of drugs to keep oral cavity or oropharynx cancer from forming or coming back. The use of ACTOplus met XR may slow disease progression in patients with oral cavity or oropharynx cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether 14-21 days of treatment with ACTOplus met XR will result in a decrease in proliferation index (Ki-67) expression in oral cavity/oropharyngeal tumor tissue as compared to placebo.

GROUP I: Patients receive ACTOplus met XR orally (PO) once daily (QD) for 14-21 days in the absence of disease progression or unacceptable toxicity. Patients may continue ACTOplus met XR PO QD for a maximum of 25 days if end of treatment biopsy/surgical treatment is delayed beyond day 22.

Patients receive ACTOplus met XR PO QD for 14-21 days in the absence of disease progression or unacceptable toxicity. Patients may continue ACTOplus met XR PO QD for a maximum of 25 days if end of treatment biopsy/surgical treatment is delayed beyond day 22.

Participant has a newly diagnosed, histologically confirmed, stage I-IV squamous cell carcinoma of the oral cavity or oropharynx and will be undergoing definitive surgical, radiotherapy, or chemoradiation treatment OR

Participant has a lesion in the oral cavity or oropharynx that is not yet biopsied but is highly suspicious for cancer; (randomization will be placed on hold until the presence of cancer is histologically confirmed, a standard of care staging PET/CT scan is completed and a treatment plan is established; if the presence of cancer is not confirmed, the participant will be considered a screen failure)

The participant's primary tumor is accessible to biopsy in the outpatient clinic setting and the participant is willing to have baseline and end of study (day 15-26) 4 mm punch biopsies of tumor and adjacent visually normal appearing tissue for biomarker analysis

If the participant has a biopsy-confirmed cancer, the baseline biopsy to collect tissue for biomarker analysis will be in addition to the pre-study diagnostic biopsy

If the participant is having surgical treatment, the end of study biopsies may be collected at the time of surgery unless surgery is delayed beyond day 26

If the participant is not having surgical treatment, the end of study biopsies will be collected prior to initiation of non-surgical treatment

Participant is able to complete a minimum of 14 days of study agent dosing prior to initiation of definitive treatment for their cancer

Participant is scheduled for an end of study biopsy within 22 days of starting study agent and within 36 days of their study screening visit; (if the participant is scheduled for surgical excision of the tumor and the surgery is delayed for any reason after the participant has started taking the study agent, study agent dosing may be extended up to a maximum of 25 days without compromising the evaluability of the end of study biomarkers)

A standard of care staging PET/CT scan has been or will be performed prior to randomization

Participant is willing and able to have another FDG PET/CT performed within 36 hours of their day 15-26 end of study biopsy

Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1

Life expectancy is > 6 months

Body mass index (BMI) is >= 18.5

Hemoglobin >= 10 g/dl

White blood cells >= 3,000/microliter

Platelets >= 100,000/microliter

Total bilirubin within normal institutional limits

With the exception of candidates with a diagnosis of Gilbert's disease in which case the total bilirubin may extend up to 1.5 x institutional upper limit of normal

Participant is willing and able to participate for the duration of the study

Participant of childbearing potential agrees to use adequate contraception (a hormonal method that has been in continual use for a minimum of 3 months prior to the study screening visit, a barrier method, or abstinence) for the duration of their study participation; (should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately)

NOTE: participants should not start hormonal therapy for the purpose of meeting the eligibility criteria for this protocol

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

Participant has received or will receive some form of treatment for their cancer prior to completing a minimum of 14 days of study agent dosing; (a biopsy is not considered a form of treatment)

Participant has a concurrent diagnosis of type I or type II diabetes that is being treated with insulin or an oral antidiabetic agent; (participants whose type II diabetes is controlled with diet and/or exercise alone are eligible provided they meet all other eligibility criteria)

Participant has taken any of the following medications within the past 3 months:

Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ACTOplus Met XR

Participant has a contraindication to biopsy

Participants with a history of congestive heart failure or New York Heart Association (NYHA) class III or IV functional status are excluded

Participant has a history of liver disease

Participant has > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 limb edema (5 - 10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection)

Participant has a history of hypoglycemia

Participant is an active alcoholic or consumes excessive amounts of alcohol per the following definitions:

Female: More than 3 drinks on any day or a total of more than seven drinks in a week

Male: More than 4 drinks on any day or a total of more than 14 drinks in a week

1 drink =

Beer: 12 oz. (1 standard size can or bottle)

Wine: 5 oz. (one standard glass)

Spirits: 6 oz. (one mixed drink or one 1.5 fluid oz. shot)

Participant has a history of macular edema

Participant has a history of bladder cancer (including in situ bladder cancer)

Participant has a history of invasive cancer (other than non-melanoma skin cancer or cervical cancer in situ) active within 18 months prior to the baseline study visit; (participants who have a history of cancer that was curatively treated without evidence of recurrence in the 18 months prior to the baseline study visit are considered eligible)

Participant is pregnant, breast feeding or planning to become pregnant; (all participants of childbearing potential regardless of method of birth control must have a negative pregnancy test at baseline; a woman is considered not to be of childbearing potential is she has had a hysterectomy, bilateral oophorectomy, or if she is > 55 years of age with >= 2 years of amenorrhea)

Breastfeeding should be discontinued if the mother is treated with ACTOplus met XR